Self-assembled doxorubicin prodrug riding on the albumin express train enable tumor targeting and bio-activation.

Doxorubicin (DOX) is a vital anthracycline chemotherapeutic drug, yet presenting significant challenges due to its severe cardiotoxicity. While Doxil enhances the pharmacokinetics and reduces the cardiotoxicity of DOX solution (DOX sol), it shows limitations of low drug loading capacity and inadequate cellular uptake. To overcome these issues, this study developed a novel disulfide bond-linked DOX-maleimide prodrug (DSSM). DSSM could self-assemble into nanoparticles (NPs) with a high drug loading capacity (58.89 %, w/w). DSSM could rapidly bind to endogenous albumin through the maleimide group. Compared to DOX sol, DSSM had increased area under the curve (AUC) by approximately 60-fold, and similarly, quadrupled tumor accumulation after 4 h of administration, achieving efficient tumor targeting. With only 5 % DSPE-mPEG, the cellular uptake of DSSM NPs was better than Doxil. Furthermore, the high reduction sensitivity of the disulfide bond enabled bio-activation of DSSM at the tumor site, while maintaining stability in normal cells. Compared with DOX sol and Doxil, DSSM NPs significantly improved safety and demonstrated better anti-tumor effect at tolerated doses. Our findings present a promising strategy for achieving effective tumor targeting and bio-activation, addressing key limitations of current DOX nanoformulations.